Multipoint Nonparametric Linkage Analysis Research Articles

Genome‐widely significant evidence of linkage of schizophrenia to chromosomes 2p24.3 and 6q27 in an SNP‐Based analysis of Korean families

The present study reports the results of a genome-wide SNP linkage scan for schizophrenia in the Korean population. Fifty-six multiplex schizophrenia families were analyzed. Clinical evaluations on all subjects were consistently performed by raters in a single research team. Multipoint non-parametric linkage analysis was performed, and empirical simulations were generated to determine genome-wide significance. The authors found genome-widely significant evidence of linkage for schizophrenia to chromosomes 2p24.3 (NPL Z = 3.18) and 6q27 (NPL Z = 2.90). Six other chromosomal regions, that is, 3q24, 13q12.3, 18q22.3, 20p12.2, 4p14, and 1p36.12, yielded NPL Z scores of above 2.0 for either broad or narrow phenotype classes. Although linkage to these loci has not received prominent attention in studies on Caucasian families, multiple overlaps were observed between our loci (on 2p, 3q, and 13q) and linkage peaks generated from extended families in various isolated populations. Fine mappings and the detection of candidate genes within these regions are warranted.

An International Collaborative Family-Based Whole-Genome Linkage Scan for High-Grade Myopia

Several nonsyndromic high-grade myopia loci have been mapped primarily by microsatellite markers and a limited number of pedigrees. In this study, whole-genome linkage scans were performed for high-grade myopia, using single nucleotide polymorphisms (SNPs) in 254 families from five independent sites. Genomic DNA samples from 1411 subjects were genotyped (Linkage Panel IVb; Illumina, San Diego, CA). Linkage analyses were performed on 1201 samples from 10 Asian, 12 African-American, and 221 Caucasian families, screening for 5744 SNPs after quality-control exclusions. Two disease states defined by sphere (SPH) and spherical equivalence (SE; sphere+cylinder/2) were analyzed. Parametric and nonparametric two-point and multipoint linkage analyses were performed using the FASTLINK, HOMOG, and MERLIN programs. Multiple stratified datasets were examined, including overall, center-specific, and race-specific. Linkage regions were declared suggestive if they had a peak LOD score >or= 1.5. The MYP1, MYP3, MYP6, MYP11, MYP12, and MYP14 loci were replicated. The novel region q34.11 on chromosome 9 (max NPL= 2.07 at rs913275) was identified. Chromosome 12, region q21.2-24.12 (36.59 cM, MYP3 locus) showed significant linkage (peak HLOD = 3.48) at rs337663 in the overall dataset by SPH and was detected by the Duke, Asian, and Caucasian subsets as well. Potential shared interval was race dependent-a 9.4-cM region (rs163016-rs1520724) driven by the Asian subset and a 13.43-cM region (rs163016-rs1520724) driven by the Caucasian subset. The present study is the largest linkage scan to date for familial high-grade myopia. The outcomes will facilitate the identification of genes implicated in myopic refractive error development and ocular growth.

Refinement of a quantitative gene locus on equine chromosome 16 responsible for osteochondrosis in Hanoverian warmblood horses

Osteochondrosis (OC) is an inherited developmental disease in young horses most frequently observed in thoroughbreds, trotters, warmblood and coldblood horses. Quantitative trait loci (QTL) for equine OC have been identified in Hanoverian warmblood horses employing a whole genome scan with microsatellites. A QTL on ECA16 reached the genome-wide significance level for hock osteochondrosis dissecans (OCD). The aim of this study was to refine this QTL on ECA16 using an extended marker set of 34 newly developed microsatellites and 15 single nucleotide polymorphisms (SNPs). We used the same 14 paternal half-sib groups as in the above-mentioned whole genome scan. The QTL for OCD in hock joints on ECA16 could be delimited at an interval between 17.60 and 45.18 Mb using multipoint non-parametric linkage analyses. In addition, six microsatellites and one SNP were significantly associated with hock OCD in the QTL region between 24.26 and 42.41 Mb. Furthermore, our analysis revealed a second QTL for fetlock OC between 6.55 and 24.26 Mb on ECA16. This report is a further step towards unravelling the genes underlying QTL for equine OC and towards the development of a marker test for OC in Hanoverian warmblood horses.

Linkage Analysis with Dense SNP Maps in Isolated Populations

Objective: SNP maps are becoming the gold standard for genetic markers, even for linkage analyses. However, because of the density of SNPs on most high throughput platforms, the resulting significant linkage disequilibrium (LD) can bias classical nonparametric multipoint linkage analyses. This problem may be even stronger in population isolates where LD can extend over larger distances and with a more stochastic pattern. We investigate the issue of linkage analysis with SNPs from the Affymetrix 500K GeneChip array in extended families from the isolated Hutterite population. Methods: We minimized LD between SNPs by two methods based on a LD block pattern (Merlin and SNPLINK) and by MASEL, a new algorithm that we proposed to select SNP subsets with minimum LD and with no prior hypothesis about the LD pattern. Results: Simulations, performed using the real LD pattern observed in the Hutterite population, show that sizeable inflation of linkage statistics persist when LD between SNPs is minimized by Merlin and SNPLINK. Inflation of linkage statistics is better controlled with MASEL. Conclusion: In this population, it may be difficult to extract from standard GeneChip arrays a SNP map without LD-driven bias that is more informative than a dense microsatellite map.

A multiple splitting approach to linkage analysis in large pedigrees identifies a linkage to asthma on chromosome 12

Large genealogies are potentially very informative for linkage analysis. However, the software available for exact non-parametric multipoint linkage analysis is limited with respect to the complexity of the families it can handle. A solution is to split the large pedigrees into sub-families meeting complexity constraints. Different methods have been proposed to "best" split large genealogies. Here, we propose a new procedure in which linkage is performed on several carefully chosen sub-pedigree sets from the genealogy instead of using just a single sub-pedigree set. Our multiple splitting procedure capitalizes on the sensitivity of linkage results to family structure and has been designed to control computational feasibility and global type I error. We describe and apply this procedure to the extreme case of the highly complex Hutterite pedigree and use it to perform a genome-wide linkage analysis on asthma. The detection of a genome-wide significant linkage for asthma on chromosome 12q21 illustrates the potential of this multiple splitting approach.

Genetic epidemiology of subclinical cardiovascular disease in the diabetes heart study.

A genome-wide linkage scan of 357 European American (EA) and 72 African American (AA) pedigrees multiplex for type 2 diabetes mellitus (T2DM) was performed with multipoint nonparametric QTL linkage analysis. Four subclinical measures of cardiovascular disease (CVD): coronary artery (CCP), carotid artery (CarCP), and abdominal aortic calcified plaque (AACP) and carotid artery intima-media thickness (IMT) were mapped. Analyses were adjusted for age, gender, body mass index, and (if appropriate) ethnicity and diabetes status. Evidence for linkage was observed in EA T2DM subjects to CarCP near 16p13 (LOD=4.39 at 8.4 cM; P = 0.00001). When all EA subjects were included, the LOD score was 2.52, suggesting an amplification of the linkage by diabetes. Linkage analysis of a principal components measure of vascular calcium (LOD = 3.85 at 9.3 cM on 16p in EA T2DM subjects) and bivariate analysis of CarCP X IMT (LOD = 3.77 at 9.3 cM on 16p in EA T2DM subjects) were consistent with this linkage. In addition, evidence for linkage was observed with CCP near D15S1515 (LOD = 2.34) in EAs. Additional loci on chromosomes 1, 2, 7, 10, 13, and 21 had LODs > 2.0. The identification of trait-determining polymorphisms underlying these linkages will help delineate risk factors for CVD in T2DM and the general population.

COMT GENOTYPE AND CONTEXT PROCESSING IN SCHIZOPHRENIA, RELATIVES AND CONTROL SUBJECTS

Catechol-O-methyltransferase is a candidate in the predisposition to schizophrenia both because of its function and the position of its gene. A multipoint non-parametric linkage analysis and a transmission disequilibrium test were performed on 42 multiplex families genotyped for Pml I and Bcl I polymorphisms using two definitions of the affected phenotype. Neither linkage nor preferential transmission of any allele or haplotype was detected, failing to replicate previous positive findings.

Genome-wide Linkage Scan in Fuchs Endothelial Corneal Dystrophy

To perform a genome-wide linkage screen with a single-nucleotide polymorphism (SNP) linkage panel to identify regions of genetic linkage in Fuchs endothelial corneal dystrophy (FECD) and to analyze affected individuals for mutations in the COL8A2 gene. Ninety-two individuals from 22 families with FECD were identified from our multiplex FECD family cohort. A genome-wide linkage scan was performed using an SNP linkage panel. Parametric two-point linkage analyses were calculated and nonparametric multipoint linkage analyses were performed on chromosomes with two-point LOD scores (HLOD) > 1.0. All affected individuals were analyzed for the two previously reported FECD mutations in the COL8A2 gene (L450W and Q455K). The genome-wide analysis identified five regions with linkage signals from all analyses on chromosomes 1, 7, 15, 17, and X. The highest two-point HLODs were found on the long arm of chromosome 15 with an HLOD of 3.26 for the recessive model and 2.48 for the dominant model. Multipoint linkage analysis also identified a linkage peak on the long arm of chromosome 15 with a LOD > 1. The region of linkage on chromosome 1p, driven by two multigenerational FECD families with a two-point LOD > 2, was adjacent to the previously identified COL8A2 gene; however, the two reported mutations in COL8A2 were not identified in any of the 56 affected individuals in the 92 samples tested. Genome-wide linkage analysis was used to identify potential linkage regions on chromosomes 1, 7, 15, 17, and X for FECD. The previously reported mutations in the COL8A2 gene were not found in the 92 samples tested.

Follow-up analysis of 180 Chinese Han families: identification of a novel locus for psoriasis at 2p22.3-11.2

Psoriasis is a common inflammatory and hyperproliferative skin disease. The pathogenesis of psoriasis remains obscure. Family and twin studies have suggested a strong genetic susceptibility to psoriasis. Eight linkage loci (PSORS1-7, PSORS9) were identified and accepted by the OMIM and an additional 16 susceptibility loci have been suggested so far. To investigate further three suggested psoriasis susceptibility loci at 2p22.3-11.2, 13q21-32 and 17q22-25.3 in a Chinese population. Using an expanded sample of 180 Chinese families with psoriasis and improved marker coverage, we verified whether they were Chinese Han psoriasis susceptibility loci. In total, 180 Chinese Han families with psoriasis vulgaris (including the 61 families used in the original genome-wide scan and 119 new families) were recruited from the Dermatology Department at the First Hospital Affiliated to Anhui Medical University. Two-point and multipoint parametric and nonparametric linkage (NPL) analyses were performed at 2p, 13q and 17q in the total 180 families as well as the 61 original and 119 new families separately. At the region 2p, a maximum multipoint NPL score of 4.11 was identified at locus D2S337 (P=0.000003), and a maximum multipoint heterogeneity LOD (HLOD) score of 4.93 (alpha=54%) was identified at the same locus in the analysis of the 180 families. However, the analysis of the 180 families did not identify any significant linkage evidence at the region 13q21-32 [a maximum multipoint HLOD score of 0.10 (alpha=7%) and NPL score of 0.95 (P=0.14)] or the region 17q22-25.3 [a maximum multipoint HLOD score of 0.08 (alpha=6%) and NPL value of 0.94 (P=0.14)]. For these two regions, the LOD scores from the 180 families as well as the 119 new families were much smaller than the ones obtained from the original 61 families. Our study indicates that 2p22.3-11.2 is a novel psoriasis susceptibility locus in the Chinese Han population and confirms that psoriasis is a genetically heterogeneous disease.

Linkage and association analyses of intragenic SNPs in the canine β‐crystallin genes CRYBB1, CRYBB2, CRYBB3, CRYBA1 and CRYBA4 with primary cataracts in wire‐haired Dachshunds

Table S1 Nucleotide polymorphisms within the canine CRYBB1, CRYBB2, CRYBB3, CRYBA1 and CRYBA4 genes with their mean polymorphism information content (PIC) and mean observed heterozygosity (HET) as well as their primer pairs, product sizes and annealing temperatures (Ta). Table S2 Multipoint non-parametric linkage analysis, polymorphism information content (PIC) and association analysis for genotypes in the three wire-haired Dachshund families using 23 intragenic single nucleotide polymorphisms (SNPs) for CRYBB1, CRYBB2, CRYBB3, CRYBA1 and CRYBA4. Please note: Blackwell Publishing is not responsible for the content or functionality of any supplementary materials supplied by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Abstract 2721: Linkage of Left Ventricular Outflow Tract Obstruction to Xq28 in 3 French-Canadian Pedigrees

BACKGROUND: Statistical genetic analysis of cohorts with left ventricular outflow tract obstruction (LVOTO) shows high heritability of such lesions. We have identified three X-linked French-Canadian pedigrees with a total of 54 family members with multiple cases of LVOTO and septal defects. AIMS: The aim of this study was to evaluate the three pedigrees with LVOTO and septal defects for genetic linkage to the X chromosome. METHODS: Detailed family history, physical exam, ECG, echocardiography and chart review was performed. Informed consent was obtained from all participants. Genomic DNA was isolated from peripheral blood samples. Twenty-four STR markers from the X chromosome were genotyped. We used a dominant genetic model with the following penetrances: 0.99 for homozygous women, 0.75 for heterozygous women, 0.99 for hemizygous men. Phenocopy rate was set to 0.01 and disease allele frequency to 0.001. Reference allele frequencies from the Quebec population were used. Analyses were performed with MLINK and MERLIN. RESULTS: Sixteen family members were affected (13 males, 3 females). Predominant lesions were atrial (n = 5) and ventricular (n = 6) septal defects, coarctation (n = 4) and aortic lesions (stenosis (n = 4), bicuspid/abnormal aortic valve (n = 6)), as well as mitral valve lesions (n = 4). Males had a high incidence of supraventricular arrhythmias postoperatively (4 with atrial flutter/fibrillation, one with ICD implantation). LOD scores above 2 were obtained in parametric two-point linkage analysis for 3 markers in the Xq28 region. Multipoint non-parametric linkage analysis confirmed these results with a NPL score of 9.1 (P < .00001) over a STR marker in intron 13 of the F8C gene. Haplotype analysis allowed the definition of a candidate interval flanked by marker DXS8069 spanning to the telomeric end of Xq. CONCLUSIONS: By analysing 3 multi-generation French-Canadian pedigrees, we mapped a syndrome of LVOTO and septal defects to the Xq28 region. Further work will refine our candidate region with dense SNP coverage to search for a shared haplotype identical by descent between the three French Canadian families, to complete the sequencing of candidate genes including FLNA, and to search for a possible founder effect in our population.

No evidence of linkage between 7q33–36 locus (OTSC2) and otosclerosis in seven British Caucasian pedigrees

The aetiology of otosclerosis is complex, and probably involves an interaction between genes and environmental factors. Previous studies have revealed genetic linkage with a number of chromosome regions, including position 7q33-36. To confirm whether linkage exists between otosclerosis and chromosome region 7q33-36. Seven multiply affected families were ascertained. Deoxyribonucleic acid from members of these families was extracted, and six markers were genotyped to cover a 16 cM region at 7q33-36. Both parametric and non-parametric multipoint linkage analyses were performed. Parametric multipoint linkage analysis excluded any linkage at 7q33-36 (logarithm of odds score <-4.0). Non-parametric linkage analysis also failed to confirm any linkage (non-parametric linkage < 1.66). When tested individually, pedigree four was the only one to show a significant non-parametric linkage score between D7s684 and D7s2513 (non-parametric linkage = 1.96). No linkage was detected between otosclerosis and the 7q33-36 region. This could be explained by the study's lack of power, due to the limited number of families available.

Examining the effect of linkage disequilibrium between markers on the Type I error rate and power of nonparametric multipoint linkage analysis of two-generation and multigenerational pedigrees in the presence of missing genotype data.

Because most multipoint linkage analysis programs currently assume linkage equilibrium between markers when inferring parental haplotypes, ignoring linkage disequilibrium (LD) may inflate the Type I error rate. We investigated the effect of LD on the Type I error rate and power of nonparametric multipoint linkage analysis of two-generation and multigenerational multiplex families. Using genome-wide single nucleotide polymorphism (SNP) data from the Collaborative Study of the Genetics of Alcoholism, we modified the original data set into 30 total data sets in order to consider six different patterns of missing data for five different levels of SNP density. To assess power, we designed simulated traits based on existing marker genotypes. For the Type I error rate, we simulated 1,000 qualitative traits from random distributions, unlinked to any of the marker data. Overall, the different levels of SNP density examined here had only small effects on power (except sibpair data). Missing data had a substantial effect on power, with more completely genotyped pedigrees yielding the highest power (except sibpair data). Most of the missing data patterns did not cause large increases in the Type I error rate if the SNP markers were more than 0.3 cM apart. However, in a dense 0.25-cM map, removing genotypes on founders and/or founders and parents in the middle generation caused substantial inflation of the Type I error rate, which corresponded to the increasing proportion of persons with missing data. Results also showed that long high-LD blocks have severe effects on Type I error rates.

A German genome-wide linkage scan for type 2 diabetes supports the existence of a metabolic syndrome locus on chromosome 1p36.13 and a type 2 diabetes locus on chromosome 16p12.2

The aim was to identify type 2 diabetes susceptibility regions in 250 German families. We conducted a genome-wide linkage scan using 439 short tandem repeat polymorphisms at an average resolution of 7.76 +/- 3.80 cM (Marshfield). In an affected-only-design (affected sib pairs), we performed nonparametric multipoint linkage analyses. Conditional analyses were applied where linkage signals were found in the baseline analyses. We identified two loci with nominal evidence for linkage on chromosomes 1p36.13 and 16p12.2 (D1S3669, 37.05 cM, logarithmic odds ratio [LOD] = 1.49, p = 0.004; D16S403, 43.89 cM, LOD = 1.85, p = 0.002). D16S403 crossed the empirically obtained threshold of genome-wide suggestive significance of LOD = 1.51. Positive findings in those regions have been reported by the following other linkage studies on: (1) symptomatic/clinical gall bladder disease with type 2 diabetes in Mexican Americans from the San Antonio Family Diabetes/Gallbladder Study (LOD = 3.7, D1S1597-D1S407, 29.93-33.75 cM); (2) body size-adiposity in another Mexican American population (D1S1597, LOD = 2.53, 29.93 cM); (3) lipid abnormalities (LOD = 3.1, D1S2826-D1S513, 41.92-60.01 cM); and (4) hypertension in Australian sib pairs (LOD = 3.1, D1S2834-D1S2728, 31.02-33.75 cM); as well as (5) a meta-analysis of four European type 2 diabetes-related genome scans (LOD = 1.09, D16S412, 42.81 cM). In linkage analyses conditional on evidence for linkage at D16S403 we identified a LOD increase (Delta LOD) of 1.55 (p = 0.0075) at D17S2180. Similar conditioning on D17S2180 revealed evidence for interaction with D1S3669 (Delta LOD = 1.67, p = 0.0055), D16S403 (Delta LOD = 1.48, p = 0.0091) and another locus on chromosome 1 where several genome scans have reported evidence for linkage ( approximately 200 cM, Delta LOD = 1.60, p = 0.0066). Our results and the findings of other studies are consistent with the presence of a locus for a complex metabolic syndrome on chromosome 1p36.13.

Linkage to chromosome 11p12 in two Maltese families with a highly penetrant form of osteoporosis

Osteoporosis is a metabolic bone disease with a strong genetic component. Family-based linkage studies were performed by a number of investigators to try to identify loci that might contain genes responsible for an increased susceptibility to osteoporosis. A whole-genome linkage scan using 400 microsatellite markers was performed in 27 members from two Maltese families with a highly penetrant form of osteoporosis. The phenotype was defined by lumbar and femoral z-scores calculated after measurement of bone mineral density by DEXA. Both males and females were among the affected individuals. Multipoint parametric and non-parametric linkage analyses were performed by EasyLinkage v4.01 using GENEHUNTER v2.1, assuming dominant and recessive modes of inheritance with variable penetrance. Evidence of linkage was observed to a marker at 11p12 where a non-parametric LOD score of 5.77 (P=0.0006) was obtained. A maximum heterogeneity LOD score of 2.55 for this region was obtained for the dominant mode of inheritance with 90% penetrance and a phenocopy rate of 1%. Following fine mapping, the critical interval was narrowed to a region that is 52.94 cM from 11p-telomere. In this region, the gene for tumour necrosis factor receptor-associated factor 6 (TRAF6) is located approximately 1 cM away from the indicated marker. Sequencing of the promoter region and exons of the TRAF6 gene revealed three sequence variants, one of which was found in three affected members within one family.

Linkage of Graves’ disease to the human leucocyte antigen region in the Chinese‐Han population in Taiwan

To investigate whether markers in the candidate chromosome regions, including the human leucocyte antigen (HLA) region, are linked to Graves' disease (GD). A familial linkage study with a candidate region approach. A total of 536 individuals in 122 multiplex Chinese-Han families with a GD proband and at least one other affected sibling, resulting in 270 affected sib-pairs. Subjects with a family history of noniatrogenic hypothyroidism or Hashimoto's thyroiditis were excluded. We genotyped eight short tandem repeat polymorphism (STRP) markers in a 13.7 cM region covering the HLA region on chromosome 6p21 and 26 STRPs in four other candidate regions previously reported in the literature. Multipoint nonparametric linkage (NPL) analysis showed significant linkage to the HLA region [the marker UniSTS:239159, nonparametric log of odds (LOD) score 3.44, P = 0.00003; NPL Z-score 4.1, P = 0.00002] from 270 affected sib-pairs. The 1-LOD support interval comprised the whole HLA region (ca. 4 Mb). By contrast, the maximal NPL Z-scores of the markers of the other candidate regions (2q33, 5q31, 7q22 and 14q31) previously reported were all less than 1.0. Our results provide strong support for linkage of GD to the HLA region. Further dissection of this region to identify the candidate gene for GD is warranted in our population.

A genome‐wide scan for modifier loci in schizophrenia

The purpose of this study was to detect genetic loci that influence clinical features of, but not necessarily susceptibility to, psychotic illness. In the Irish Study of High-Density Schizophrenia Families (n = 270 families, n = 1,408 individuals), subjects with non-affective psychosis were rated using the Operational Criteria Checklist for Psychotic Illness. Factor analysis identified hallucinations, delusions, and negative, manic, and depressive symptom factors. We performed autosomal genome-wide multipoint non-parametric quantitative trait locus linkage analysis, in affected individuals only, using these five factors, as well as age at onset, and course of illness. Determination of empirical significance and correction for multiple testing was implemented using 200 simulated genome scans. We also tested for pleiotropic loci by examining the sums of -log(10)'s of the empirical P values of multiple traits in selected regions. LODs of 2.42 and 2.35 were obtained near D9S934 (9q33.1) and D14S587 (14q24.2), respectively, for course of illness, and of 2.26 between D6S1040-D6S2420 (6q23.1-25.1) and age at onset. No other regions met criteria for suggestive linkage to any one trait. No loci were significant after correction for multiple testing. On 6q, however, the joint linkage of age of onset, course, delusions, and depressive symptoms resulted in a genome-wide P = 0.06. We conclude that genes located near 9q33.1 and 14q24.2 may modify the clinical course and severity of schizophrenia. A gene in 6q may affect several clinical features of illness.

Genome-Wide Linkage Scan of Common Stroke in Families From Northern Sweden

Taking advantage of low genetic variations in northern Sweden, we performed a genome-wide linkage scan to investigate the susceptibility loci for common forms of stroke. Fifty-six families, containing multiple cases of stroke and whose data had been previously used to replicate linkage to the phosphodiesterase 4D locus on chromosome 5q, were genotyped in a genome-wide scan. Fine mapping was performed, and subsequently 53 additional families from the same region were genotyped over the candidate regions. Linkage calculations were performed by using 3 different disease models, from a very broad (all stroke cases defined by World Health Organization MONICA criteria) to a narrower (ischemic stroke only) stroke phenotype. With all models, nonparametric multipoint linkage analysis yielded allele-sharing log of the odds (LOD) scores >1.2 at 9 locations: 1p34, 5q13, 7q35, 9q22, 9q34, 13q32, 14q32, 18p11, and 20q13. The highest allele-sharing LOD scores were obtained on chromosomes 5q (previously reported), 1p (LOD=2.09), and 18p (LOD=2.14). Fine mapping resulted in increased allele-sharing LOD scores for chromosome 5q (previously reported) and 9q22 (LOD=1.56), but all others decreased. Combining these initial results with a subsequent analysis of 53 additional families, we obtained the highest allele-sharing LOD scores on chromosomes 5q, 13q, and 18p, although none reached the initial genome-wide allele-sharing LOD scores. Genetic analysis of stroke in families from northern Sweden did not identify any new major stroke loci. This indicates that multiple minor susceptibility loci in addition to the previously known locus on chromosome 5 could contribute to the disease.

A genome‐wide scan for schizophrenia and psychosis susceptibility loci in families of Mexican and Central American ancestry

Schizophrenia is a complex psychiatric disorder, likely to be caused in part by multiple genes. In this study, linkage analyses were performed to identify chromosomal regions most likely to be associated with schizophrenia and psychosis in multiplex families of Mexican and Central American origin. Four hundred and fifty-nine individuals from 99 families, containing at least two siblings with hospital diagnoses of schizophrenia or schizoaffective disorder, were genotyped. Four hundred and four microsatellite markers were genotyped for all individuals and multipoint non-parametric linkage analyses were performed using broad (any psychosis) and narrow (schizophrenia and schizoaffective disorder) models. Under the broad model, three chromosomal regions (1pter-p36, 5q35, and 18p11) exhibited evidence of linkage with non-parametric lod (NPL) scores greater than 2.7 (equivalent to empirical P values of less than 0.001) with the peak multipoint NPL = 3.42 (empirical P value = 0.00003), meeting genomewide evidence for significant linkage in the 1pter-p36 region. Under the narrow model, the same three loci showed (non-significant) evidence of linkage. These linkage findings (1pter-p36, 18p11, and 5q35) highlight where genes for psychosis and schizophrenia are most likely to be found in persons of Mexican and Central American ancestry, and correspond to recent linkages of schizophrenia or psychosis in other populations which were formed in part from emigrants from the Spanish empire of the 15th and 16th centuries.

Significant linkage to airway responsiveness on chromosome 12q24 in families of children with asthma in Costa Rica

Although asthma is a major public health problem in certain Hispanic subgroups in the United States and Latin America, only one genome scan for asthma has included Hispanic individuals. Because of small sample size, that study had limited statistical power to detect linkage to asthma and its intermediate phenotypes in Hispanic participants. To identify genomic regions that contain susceptibility genes for asthma and airway responsiveness in an isolated Hispanic population living in the Central Valley of Costa Rica, we conducted a genome-wide linkage analysis of asthma (n = 638) and airway responsiveness (n = 488) in members of eight large pedigrees of Costa Rican children with asthma. Nonparametric multipoint linkage analysis of asthma was conducted by the NPL-PAIR allele-sharing statistic, and variance component models were used for the multipoint linkage analysis of airway responsiveness as a quantitative phenotype. All linkage analyses were repeated after exclusion of the phenotypic data of former and current smokers. Chromosome 12q showed some evidence of linkage to asthma, particularly in nonsmokers (P < 0.01). Among nonsmokers, there was suggestive evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 2.33 at 146 cM). After genotyping 18 additional short-tandem repeat markers on chromosome 12q, there was significant evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 3.79 at 144 cM), with a relatively narrow 1.5-LOD unit support interval for the observed linkage peak (142-147 cM). Our results suggest that chromosome 12q24.31 contains a locus (or loci) that influence a critical intermediate phenotype of asthma (airway responsiveness) in Costa Ricans.